1. Field of the Invention
The present invention relates to a pharmaceutical composition for preventing or treating a human cytomegalovirus (HCMV) infectious disease, which includes a notch-target protein or a gene encoding the same as an active ingredient.
2. Discussion of Related Art
HCMV which is known as herpes virus-5 has a high species specificity with respect to culture cells unlike herpes simplex and is proliferated only in human fetal fibroblasts. Globally occurring in about 1% of new borns, the HCMV infection novel is one of the most common congenital infections, and 40% of the population is infected with the HCMV. About 10 to 15% of the congenital HCMV infections have symptoms, and 50 to 90% of the infections with symptoms have side effects such as mental retardation or sensorineural deafness.
Korea Centers for Disease Control and Prevention says that disease incidences caused by infection are very high in Europe and U.S., and 95% or more of adults in Korea have a disease in a subclinical incubation state, but the disease occurrence in Korea is lower than those of the Europe and the U.S. However, it is known that, in the case of people who get immuno-inhibitor injection after leukemia, a cancer, immunodeficiency and organ transplantation, the incubation state is reactivated causing a disease such as retinitis, infection, or colitis. Particularly, the number of organ transplantation patients in Korea is on the growing trend every year, and thus the importance of a therapeutic agent against HCMV further stands out.
When healthy people are infected with HCMVs, there may be no symptom, but when infants or immuno-deficient patients who have relatively weak immunity, are infected with HCMVs, serious symptoms may develop. Particularly, the HCMVs are known as a cause of further deterioration of malignant tumors including a brain tumor, a colon cancer, a breast cancer, etc.
The HCMVs influence the liver, brain, lung, ears or eyes, and HCMV infectious diseases include pneumonia, cytomegaloviral mononucleosis, cytomegaloviral retinitis, cytomegaloviral hepatitis, cytomegaloviral infection, and cytomegaloviral antigenemia, etc. Until now, as a treatment method for a HCMV infectious disease, the use of an anti HCMV drug, the administration of an antiviral agent, or the administration of an immunoglobulin had been mainly used. However, such conventional treatment methods have an inconvenience of monitoring a period of treating blood and kidney functions or a liver function, and a problem of targeting an HCMV infectious disease other than cancer.
Meanwhile, a notch derived from a gene making a groove of the wing of a drosophila by inducing excessive growth in a notch mutation is a membrane protein structure serving as a cell surface receptor and used for rapid transduction and amplification of a signal between cells in a multicellular animal.
It is reported that the notch signaling is well conserved evolutionarily from vertebrates to invertebrates and plays an important role in determining the destiny of a cell in the early stage of development. The notch signaling is known as a key factor for regulating differentiation of nerves, eyeballs, lymph, muscles, globules, etc. and is involved in haemangiogenesis.
All of a notch receptor and ligands are membrane proteins, and the ligands and the notch receptor are linked between two adjacent cells, thereby realizing notch signaling. After two hydrolyses, in the notch receptor, a notch intracellular domain (NICD) is separated and then transferred to a nucleus. In the nucleus, NICD is a transcription repressor and linked to C-promoter binding factor 1 (CBF-1)/suppressor of hairless/lag-1 (CSL) and thereby replaces a corepressor (CoR) previously linked with the CSL. An NICD/CSL complex collects a co-activator (CoA) such as mastermind-like (MAML) or p300 and thus induces or inhibits notch target genes such as hairy/enhancer of Split (HES), hairy/enhancer-of-split related with YRPW motif protein (HEY), cyclin D1, p21, NF-κB, c-Myc, pre-T cell receptor alpha chain (pre-Ta), GATA3, NRARP and Deltex1. Here, HES is a representative target gene for notch signaling and one of the transcription factors expressed when the notch signaling pathway is activated. A Hes family includes Hes1, Hes3, and Hes5. Also, HEY is a representative notch target gene having an increased expression level by a notch signaling pathway and is included in a Hes-related family.
When such a notch signaling is activated, it is known that tumor occurs in various cancer models. It is known that, when the active notch, NICD, is expressed in a mouse stem cell, T-cell leukemia/lymphomas occurs, and about 50% of activated notch 1 has been found in T-cell acute lymphoblastic leukemia (TALL). Also, it has been reported that the notch receptor and ligands and a target for the notch signaling are activated in various cancers including uterine cervical cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, prostate cancer, and it is known that the notch 1 receptor is associated with a bad prognosis in breast cancer patients and associated with cancer metastasis in a prostate cancer.
For these reasons, studies on notch signaling-associated factors are very important for analyzing the causes of various diseases for humans and finding a treatment method therefor. Particularly, to treat a cancer or an autoimmune disease, the importance of the role of a signaling pathway such as the notch signaling pathway is emphasized.
In addition, to treat cancer or an autoimmune disease, studies on inhibiting notch signaling in various aspects have been performed, and a considerable amount of genes affecting notch signaling were found as a result of the rapid development of a scale genomic search, a proteomic analysis method and bioinformatics.
However, through such a research, the complexity of the notch signaling pathway, the interconnection with another signaling pathway, and particularly, a relationship with HCMVs have not been revealed so far.